Therapeutic Strategies Targeting Urokinase and Its Receptor in Cancer

SIMPLE SUMMARY: The uPA/uPAR system is highly involved in cancer progression and metastasis. Many studies have definitively assessed that the high expression of urokinase-type plasminogen activator (uPA) and membrane urokinase-type plasminogen activator receptor (uPAR) in patients does correlate with metastasis formation and poor prognosis. Thus, due to the key role of uPA and uPAR in cancer, it is essential to develop compounds able to interfere with and/or inhibit their activity. In this review, we discuss the role of uPA and uPAR as diagnostic, prognostic and therapeutic markers in tumors. Moreover, we describe, in-depth, the design, construction and analysis of uPA and uPAR inhibitors in in vitro and in vivo models. Clinical trials, testing some of these inhibitors, are also accurately described. ABSTRACT: Several studies have ascertained that uPA and uPAR do participate in tumor progression and metastasis and are involved in cell adhesion, migration, invasion and survival, as well as angiogenesis. Increased levels of uPA and uPAR in tumor tissues, stroma and biological fluids correlate with adverse clinic–pathologic features and poor patient outcomes. After binding to uPAR, uPA activates plasminogen to plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme able to facilitate tumor cell invasion and dissemination to distant sites. Moreover, uPAR activated by uPA regulates most cancer cell activities by interacting with a broad range of cell membrane receptors. These findings make uPA and uPAR not only promising diagnostic and prognostic markers but also attractive targets for developing anticancer therapies. In this review, we debate the uPA/uPAR structure–function relationship as well as give an update on the molecules that interfere with or inhibit uPA/uPAR functions. Additionally, the possible clinical development of these compounds is discussed.